psychologywikiaorg-20200213-history
Genetic counseling: Marfan Syndrome
Marfan Syndrome Introduction and contracting *What is your understanding of why you were referred to genetics *What are your main concerns *Explain that they are there to determine if they might have a genetic condition called Marfan syndrome and give overview of Marfan Outline session *I will begin by taking a family history *Our resident _____ will take a medical history *She and Dr. X will perform a physical examination *We will then discuss whether or not we believe a diagnosis can be made or if there are other tests that need to be performed *If a diagnosis is made we will discuss Marfan syndrome in more detail *We will also answer any questions you have Overview of Marfan syndrome *A heritable disorder of the connective tissue that affects many organ systems, including the skeleton, lungs, eyes, heart and blood vessels. *The condition affects both men and women of any race or ethnic group *occurs in 1-2 people per every 10, 000 Symptoms of Marfan syndrome *high degree of clinical variability *ocular findings: myopia, displacement of the lens, retinal detachment, glaucoma, early cataract formation *skeletal findings: bone overgrowth, joint laxity, long extremities, pectus excavatum or carinatum, scoliosis, high arched palate, positive wrist and thumb signs, reduced upper to lower segment, arm span to height ratio >1.05, flat feet *cardiovascular findings: dilatation of the aorta, aortic dissection, mitral valve prolapse, triscupsid valve prolapse, enlargement of the pulmonary artery *other systems involved: pulmonary, skin, nervous Diagnosis of Marfan *Diagnosis is made clinically (see diagnostic criteria below for details) *based on family history and the observation of characteristic findings in multiple organ systems *no family history? 2 major criteria and 1 minor (3 systems) *with a family history? 1 major and 1 minor (2 systems) *sometimes we're very confident in the diagnosis (and sometimes sure of a negative diagnosis), sometimes we're just not sure and we may follow a person for a while, sometimes we think there may be another diagnosis *What will a diagnosis mean *predisposition for aortic rupture and other heart problems so must have cardiology exams for echocardiograms (monitor aortic root growth - beta-blockers may be prescribed) *orthopedist exams (for early detection of scoliosis and pectus) *yearly ophthalmology exams (due to various eye problems that can often be treated with corrective lenses, but sometimes require surgery) *potential for complications during pregnancy (rapid progression of aortic root enlargement) must be closely monitored *50% chance that future children will inherit Marfan syndrome Age of Onset, natural history, and life span *Some signs of the syndrome are present at birth *The serious vascular complications may develop at any time from fetal life through old age and are the chief cause of death in these individuals *The use of b-adrenergic blockers has been associated with a decrease in aortic dilatation and thus increased life *The mean age for survival for men = 43 and women = 46 *However, with appropriate management, individuals are reportedly living until their 70's. Genetics *Autosomal dominant inheritance *75% have an affected parent *25% due to new mutations *The disrupted gene is FBN1 - codes for Fibrillin (a protein constituent of connective tissue). *Located at 15p21 *Molecular genetics **>100 mutations leading to abnormal splicing of the mRNA have been reported **The gene is >110 kb and is composed of 65 exons ***A common motif is the epidermal growth factor (EGF) like domain. This domain occurs 47 times ***Each EGF domain contains 6 conserved cysteine residues that from 3 disulfide bonds ***43 of the EGF domains contain a consensus sequence for calcium binding which facilitates inter and intramolecular interactions ***Mutations in any of the conserved calcium binding sequences or the conserved cysteine residues lead to classical Marfan syndrome *The syndrome is fully penetrant, although the manifestations can vary considerably Recurrance Risks *If parent affected 50% chance future children will also be affected *If parent of affected child is not affected then they have a much smaller chance of having another affected child (rare cases of germline and somatic mosaicism) Genetic Testing (available, but often not used) *Because FBN1 mutations have been detected in individuals with other fibrillinopathies, the presence of a mutation doesn't by itself confirm the diagnosis. *Mutations have not been detected in at least 25% of subjects with Marfan syndrome. *There exists the possibility that the Marfan syndrome phenotype may be produced by mutations in at least one other gene, for this reason, a definitive DNA-based test is not available *molecular genetic testing for mutations in the fibrillin-1 (FBN1) gene on chromosome locus 15q21.1 *direct mutation screen cumbersome and inefficient due to large size *up to 70% show positive results *mutation is not identified in large number of individuals with Marfan syndrome *If a specific mutation is known within a family, that specific mutation can be tested individuals suspected to be affected *many mutations in FBN1 cause phenotype different from Marfan syndrome *mutational screening available on research basis *Linkage analysis **Markers are highly informative and are within the FBN1 gene **Nearly completely informative **Not available if only one affected individual in family **Although usually informative caution needed because locus heterogeneity not definitively excluded *Protein based methods **Being explored **Further research needed to determine specificity **Immunofluorescence studies of extracellular microfibrils with fibrillin antibodies are available as diagnostic aids Prenatal Testing *Available using linkage analysis if linkage has been established in affected family members *Or using mutational analysis when disease-causing mutation has been identified *Ultrasound exam in first two trimesters cannot detect manifestations of Marfan Geneotype-Phenotype Correlations *Few and none are definitive *Those with most severe and rapid termed "neonatal Marfan syndrome" have alterations in center of gene exons 24-32 (but not all with severe form have identified mutations and others with mutations in this region have classic or mild variants of Marfan) *In general mutations causing in-frame gain or loss of coding sequence associated with more severe disease *Premature termination result in rapid degradation of transcripts associated with mild conditions that fail to meet diagnostic criteria *Individuals with mutation preventing C-terminal propeptide processing had only skeletal manifestations *Amino acid substitution may have functional or not have functional importance Diagnostic Criteria *Diganosis can be made clinically if: 2 organ systems are involved in the presence of an affected first degree relative *Or, involvement of the skeleton and two or more organ systems is required, as well as the presence of at least one major criterion *Note: skeletal system qualifies as a major criterion only if at least four major manifestations are present Clinical Features (major and minor criteria) **Skeletal (can develop in young children and progress during periods of rapid growth) *Major criteria for diagnosis: **Pectus carinatum (protruding sternum in convex shape) **Pectus excavatum requiring surgery (congenital condition in which the sternum is abnormally depressed caused by overgrowth of ribs pushing the sternum in) **Scoliosis (mild to severe and progressive may require bracing or surgery) **Reduced extension at the elbows (<170°) **Pes planus (flatfoot) **Protrusio acetabuli (pertaining to the hip bone socket where acetabulum abnormally deep and shows accelerated erosion) **Reduced upper to lower segment ratio **Wrist sign: thumb overlaps the distal phalanx of the fifth digit when grasping the contralateral wrist (due to bone overgrowth and joint laxity) **Thumb sign: entire nail of the thumb projects beyond the ulnar border of the hand when the hand is clenched without assistance. *Minor criteria: **Pectus excavatum of moderate severity **Joint hypermobility **High arched palate with crowded teeth **Specific facies: dolicocephaly, malar hypoplasia, retrognathia, down slanting palpebral fissures, deep set eyes, palate can be highly arched **Dolichostenomelia (extremities are disproportionately long for the size of the trunk) **Arachnodactyly (spider fingers long and thin) *Major criteria: **Ectopia lentis (displacement of the lens of the eye in 60% of affected and it is a hallmark feature) *Minor critieria: **Flat cornea **Increased axial length of globe **Hypoplastic iris or hypoplastic ciliary muscle *Major Criteria: **Dilitation of the ascending aorta w/ or w/o aortic regurgitation, involving the sinuses of Valsalva **Dissection of the ascending aorta *Minor criteria: **Mitral valve prolapse w/ or w/o mitral valve regurgitation **Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis before the age of 40 **Calcification of the mital annulus before age 40 **Dilatation or dissection of the descending thoracis or abdominal aorta before age 50. *Minor criteria: **Spontaneous pneumothorax (air in the pleural cavity) **Apical blebs *Minor criteria: **Striae atrophicae (stretch marks) **Recurrent or incisional hernia *Major criteria: **Lumbosacral dural ectasia by CT or MRI Management/Treatment *Growth **All individuals should be measured periodically **Prepubertal girls can have height reduction by taking high-dose estrogen therapy combined with progesterone to prevent endometrial hyperplasia *Development **Physical therapy is of value in promoting motor skill development **Psychosocial family counseling *Musculoskeletal **Delays in gross motor development caused by joint hypermobility can be ameliorated with PT and orthopedic braces (as needed) **Treatment of scoliosis and kyphosis depending on the severity of the curvature **Pectus excavatum or carinatum may need to be repaired to prevent cardiac or pulmonary compromise *Cardiovascular **Follow with a cardiologist **Echo required at frequent intervals **b-Adrenergic blaockade has been demonstrated to slow progression of the aortic root dilatation by decreasing the stress on the aortic wall and the tunica media. **Graft replacement surgery if necessary **Most adults with Marfan syndrome will eventually need replacement of the dilated aortic root (5% operative risk) and leaking aortic valve. **If mitral valve prolapse is dx., standard prophylaxis against bacterial endocarditis is recommended for all dental procedures. **Limit physical activities such as contact sports (football, basketball, hockey, volleyball, boxing, wrestling, etc.) *Ophthalmologic: **Myopia most common treated with corrective lenses **Adequate optical correction must be prescribed and worn **Assessments of refraction must be performed **Amblyopia must be treated aggressively **Lens removal for optical reasons is not recommended (the cataract of Marfan syndrome is a true indication for lens extraction) **When ectopia lentis is progressive and leads to complications such as iritis, glaucoma etc. the lens may need to be removed. **Because individuals are prone to retinal detachment, they should avoid contact sports *Neurologic **Orthostatic headache resulting from cerebrospinal fluid leakage is often transient. Treat with bed rest or corticosteroids *Respiratory **Spontaneous pneumothorax is treated by ecacuation of the intrapleural air and restoration of the negative pleural pressure by insertion of a drainage test tube. Differential *Many of the skeletal features common in general population *Other disorders caused by FBN1 mutations **MASS phenotype-myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal features **Mitral valve prolapse syndrome - MVP with or without skeletal features **Predominant aortic aneurysm with other subdiagnostic features of Marfan **Predominant or isolated skeletal features of Marfan **Dominant ectopia lentis - lens dislocation with skeletal features **Familial ectopia lentis - associates eye and skeletal features (prolonged follow-up to differentiate it from Marfan) **Shprintzen-Goldberg syndrome - skeletal and heart findings with craniosynostosis and neurodevelopmental abnormalities (this is likely a genetically heterogeneous condition) *Other connective tissue disorders share some overlap (Ehlers-Danlos syndrome, fragile X, Stickler syndrome) Should be easily distinguished by other features though Patient Resources *National Marfan Foundation :382 Main Street :Port Washington, NY 11050 :phone: 1-800-8-MARFAN :www.marfan.org *Canadian Marfan Association :1-905-826-3223 :http://www.marfan.ca References *Schrijver I, Alcorn DM, Francke U. Chapter 13. (2001). Management of Genetic Syndromes. Ed. Allanson JE, Cassidy SB. New York: Wiley-Liss, Inc. *Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company. *Geneclinics: Marfan syndrome. **Cardiovascular **Pulmonary **Skin **Dura Notes The information in this outline was last updated in 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.